A long-range flexible billboard model of gene activation.

Gene regulation is fundamentally important for the coordination of diverse biologic processes including homeostasis and responses to developmental and environmental stimuli. Transcription factor (TF) binding sites are one of the major functional subunits of gene regulation. They are arranged in cis-regulatory modules (CRMs) that can be more active than the sum of their individual effects. Recently, we described a mechanism of glucocorticoid (GC)-induced gene regulation in which the glucocorticoid receptor (GR) binds coordinately to multiple CRMs that are 10s of kilobases apart in the genome. In those results, the minority of GR binding sites appear to involve direct TF:DNA interactions. Meanwhile, other GR binding sites in a cluster interact with those direct binding sites to tune their gene regulatory activity. Here, we consider the implications of those and related results in the context of existing models of gene regulation. Based on our analyses, we propose that the billboard and regulatory grammar models of cis-regulatory element activity be expanded to consider the influence of long-range interactions between cis-regulatory modules.